Over 2/3 of the US population is obese or overweight, a condition associated with increased risk and decreased survival of various cancers including breast cancer. There is a large unmet medical need to identify mechanisms underlying the link between obesity and cancer. The purpose of these studies is to elucidate the obesity-dependent mechanisms promoting aggressive mammary tumor growth. Circulating levels of leptin, an adipocyte-secreted cytokine that regulates body weight, are elevated in obese and overweight individuals. We orthotopically transplanted tumor cells derived from primary spontaneous MMTV-Wnt-1 tumors into morbidly obese leptin-deficient (ob/ob; lack wild-type leptin) and leptin receptor-deficient (db/db; hyperleptinemic) mice. The MMTV-Wnt-1 tumors, like many human breast tumors, are mixed lineage giving rise to tumors expressing both basal and luminal tumor markers. We determined that orthotopic transplant of MMTV-Wnt-1 tumor cells into obese db/db mice, with high serum leptin, leads to accelerated tumor growth. In contrast, transplant into obese ob/ob mice leads to small, disorganized tumors. More importantly, tumors from leptin-deficient ob/ob mice are predominantly comprised of differentiated epithelial (E-cadherin) and myoepithelial (α−SMA and keratin 14) tumors cells and surprisingly lack basal (keratin 5 and 6) and luminal (keratin 8) lineage tumor cells. Indeed, we determined that AKT cell survival/proliferation pathway was suppressed in the tumors from leptin-deficient mice. The phospho-AKT (p-AKT) immunopositive cells were primarily also expressing keratin 6, and not αSMA or keratin 8, indicating that AKT is activated in the keratin 6 basal-like tumor cells. These studies are highly significant because they indicate leptin, elevated in obese patients, promotes aggressive tumor growth by targeting survival, proliferation, and/or differentiation of subpopulations of mammary tumor cells.